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Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld, Julia and Orfanos, Zacharias and Chevessier, Frédéric and Eggers, Britta and Heil, Lorena and Uszkoreit, Julian and Unger, Andreas and Kirfel, Gregor and van der Ven, Peter F. M. and Marcus, Katrin and Linke, Wolfgang A. and Clemen, Christoph S. and Schröder, Rolf and Fürst, Dieter (2020) Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation. Acta Neuropathologica Communications, 8 (1), p. 154. BioMed Central. doi: 10.1186/s40478-020-01001-9. ISSN 2051-5960.

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Official URL: https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-020-01001-9

Abstract

Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.

Item URL in elib:https://elib.dlr.de/135969/
Document Type:Article
Title:Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Schuld, JuliaInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, GermanyUNSPECIFIED
Orfanos, ZachariasInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, GermanyUNSPECIFIED
Chevessier, FrédéricInstitute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, GermanyUNSPECIFIED
Eggers, BrittaMedizinisches Proteom-Center, Ruhr-University Bochum, Bochum, GermanyUNSPECIFIED
Heil, LorenaInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, GermanyUNSPECIFIED
Uszkoreit, JulianMedizinisches Proteom-Center, Ruhr-University Bochum, Bochum, GermanyUNSPECIFIED
Unger, AndreasInstitute of Physiology II, University of Münster, Münster, GermanyUNSPECIFIED
Kirfel, GregorInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, GermanyUNSPECIFIED
van der Ven, Peter F. M.Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germanyhttps://orcid.org/0000-0002-9750-8913
Marcus, KatrinMedizinisches Proteom-Center, Ruhr-University Bochum, Bochum, GermanyUNSPECIFIED
Linke, Wolfgang A.Institute of Physiology II, University of Münster, Münster, GermanyUNSPECIFIED
Clemen, Christoph S.Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, GermanyUNSPECIFIED
Schröder, RolfInstitute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, GermanyUNSPECIFIED
Fürst, DieterInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, GermanyUNSPECIFIED
Date:4 September 2020
Journal or Publication Title:Acta Neuropathologica Communications
Refereed publication:Yes
Open Access:Yes
Gold Open Access:Yes
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:8
DOI :10.1186/s40478-020-01001-9
Page Range:p. 154
Publisher:BioMed Central
ISSN:2051-5960
Status:Published
Keywords:Myofibrillar myopathy, Mouse model, Filamin, Myofibrillar lesions, Muscle damage, BAG3, HSPB7, Pathophysiology, Autophagy
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Vorhaben Systemphysiologie (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Arndt, Carina
Deposited On:08 Sep 2020 13:19
Last Modified:30 Sep 2020 10:31

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